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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Perindopril and prevention of atrial fibrillation

Jean-Claude Tardif* and Mario Talajic

Department of Medicine, Montreal Heart Institute and Université de Montréal, 5000 Belanger Street, Montreal, Canada H1T 1C8

* Corresponding author. Tel: +1 514 376 3330; fax: +1 514 593 2500. E-mail address: jean-claude.tardif{at}icm-mhi.org


   Abstract
Top
 Abstract
Hypertension and atrial...
 Angiotensin-converting enzyme...
 Conclusion
 References
 
Atrial fibrillation (AF) is a major health problem and has been described as one of two emerging cardiovascular epidemics at the turn of the century. It is the most frequent cardiac arrhythmia, affecting 5% of individuals aged over 65 years, and it is associated with an increased risk of stroke and a doubling of mortality. Hypertension has been shown to be the most prevalent, independent, and potentially modifiable risk factor for AF. The current treatment of patients with AF is inadequate. More than 50% of patients have recurrences of the arrhythmia within 12 months despite therapy with potent anti-arrhythmic drugs, thus new strategies to prevent AF are needed. There are several lines of evidence suggesting that renin–angiotensin system (RAS) inhibition may reduce the incidence of new-onset AF as well as AF recurrence. In experimental models, angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease both atrial structural and functional remodelling and AF; these effects appear to be specific to RAS inhibition and to be independent of the haemodynamic benefits of blood pressure control. A recently published meta-analysis of 11 clinical studies suggested that RAS inhibition reduced the risk of AF occurrence by 28%. In a cohort study involving 12 000 patients with hypertension, ACE inhibition was associated with a reduced incidence of AF. The bulk of evidence to date suggests that ACE inhibition may be a novel target to prevent the recurrence of AF in patients with hypertension; however, this has not been tested in an adequately powered prospective trial. The ongoing Canadian Trial on Atrial Fibrillation–2 (CTAF-2) is therefore testing the hypothesis that perindopril, a long-acting ACE inhibitor with a high affinity for tissue ACE, will be effective in preventing recurrences of AF in patients with hypertension.

Key Words: Atrial fibrillation • Hypertension • ACE inhibition • Perindopril


   Hypertension and atrial fibrillation
Top
 Abstract
 Hypertension and atrial...
Angiotensin-converting enzyme...
 Conclusion
 References
 
Hypertension affects ~1 billion individuals worldwide. As the population ages, the prevalence of hypertension is expected to increase even further, unless broad and effective preventive measures are implemented. Recent data from the Framingham study suggest that individuals who are normotensive at 55 years of age have a 90% lifetime risk of developing hypertension.1 The relationship between blood pressure and the risk of cardiovascular disease events is continuous and independent of other risk factors. The higher the blood pressure, the greater the chance of myocardial infarction, heart failure, and stroke.2 Atrial fibrillation (AF) is also a major health problem and has been described as one of two emerging cardiovascular epidemics at the turn of the century. It is the most frequent cardiac arrhythmia, affecting 5% of individuals aged over 65 years, and it is associated with an increased risk of stroke and a doubling of mortality.3–7 The loss of effective atrial contraction may result in impaired cardiac performance, reduced exercise tolerance, and heart failure.8–11 In addition, patients with AF often have disabling palpitations.

AF and hypertension often co-exist. In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, hypertension was present in 70% of patients and was the predominant associated cardiovascular condition in 50% of patients.12 Indeed, hypertension has been shown to be the most prevalent, independent, and potentially modifiable risk factor for AF. Hypertension may trigger left ventricular hypertrophy, increased left atrial pressure, and left atrial enlargement, predisposing individuals to AF, thrombosis, and systemic embolism. The current treatment of patients with AF is inadequate: >50% of patients have recurrences of their arrhythmia within 12 months despite therapy with potent anti-arrhythmic drugs. In addition, these drugs have significant proarrhythmic activity and non-cardiac toxicity that limit their use. Although anticoagulation therapy reduces the thrombo-embolic complications of AF, many patients are not candidates for this therapy or choose to forego it. Catheter ablation therapy around the junction of the pulmonary veins in the left atrium is a promising approach, but it is currently only applicable in a small number of patients. In addition, several catheter ablations are often needed because of recurrences, and rare but clinically significant complications do occur with this strategy. Therefore, new strategies to prevent AF are needed.

There are several lines of evidence to suggest that angiotensin-converting enzyme (ACE) inhibition may reduce the incidence of new-onset AF as well as its recurrence. Angiotensin II has been shown to increase atrial pressure and stretch, which are associated with electrophysiological changes promoting AF. Angiotensin II is also a potent promoter of fibrosis through reduced collagenase activity, cardiac myoblast proliferation, and activation of extracellular, signal-regulated and mitogen-activated protein kinases, and atrial fibrosis may explain intra-atrial conduction disturbances and the persistent susceptibility to AF. In addition, increased ACE expression has been observed in the atria of patients with AF. ACE inhibition has been shown to decrease both atrial structural and functional remodelling and AF in a dog model of heart failure.13,14 In this model, these beneficial changes appeared to be specific to renin–angiotensin system (RAS) inhibition and independent of the haemodynamic benefits of blood pressure control. In patients with AF pre-treated with amiodarone, an ACE inhibitor, or an angiotensin-receptor blocker, the recurrence of AF after cardioversion was reduced.15,16 Furthermore, we have published the results from the Studies of Left Ventricular Dysfunction (SOLVD) trial that strongly indicate a beneficial effect of ACE inhibition on AF development in patients with chronic left ventricular dysfunction.17 A recently published meta-analysis of 11 studies suggested that inhibition of RAS reduced the risk of AF occurrence by 28%.18


   Angiotensin-converting enzyme inhibition and prevention of atrial fibrillation in patients with hypertension
Top
 Abstract
 Hypertension and atrial...
 Angiotensin-converting enzyme...
Conclusion
 References
 
Because experimental and early clinical studies have suggested a role for ACE inhibition in the prevention of AF, and because ACE inhibitors are among the most frequently prescribed anti-hypertensive medications, we assessed the impact of this class of drugs on the occurrence of AF in a large cohort of hypertensive patients.19 We used long-acting calcium-channel blockers as the blood pressure lowering comparator, because they represent the most frequently prescribed anti-hypertensive drug class after ACE inhibitors and because it has been suggested that they have anti-arrhythmic properties.

We performed a retrospective, longitudinal cohort study on individuals from an integrated medical and pharmacy claims database in the USA containing records for >8 million people.19 To be eligible, patients were required to have been given a diagnosis of hypertension at one or more medical visits during the 6 months before and after an index prescription of an ACE inhibitor or calcium-channel blocker. Any additional anti-hypertensive medication prescribed during the follow-up period was accepted, apart from calcium-channel blockers for ACE inhibitor patients and ACE inhibitors for calcium-channel blocker patients. The index prescriptions of ACE inhibitor or calcium-channel blocker were harvested between 1 January 1995 and 30 June 1999, and the final cohorts were evaluated up until 30 June 2002, with an average follow-up time of 4.6 years for the ACE inhibitor group and 4.2 years for the calcium-channel blocker group. Propensity scoring and logistic regression were used to match cohorts and minimize potential baseline differences that could bias the final outcomes.

A total of 5463 eligible patients were matched in each group (n = 10 926). The major baseline characteristics revealed that both groups had a mean age of 65 years; in addition, the ACE inhibitor and calcium-channel blocker groups had a 3.7 vs. 3.6% prevalence of heart failure, a 9.9 vs. 10.1% prevalence of diabetes, a 6.4 vs. 6.7% prevalence of stroke, and a 2.3 vs. 2.4% previous history of AF, respectively. Of note, ~48% of patients in both groups were receiving at least one other anti-hypertensive treatment, with a higher rate of thiazide use in the ACE inhibitor group, and a higher rate of beta-blocker use in the calcium-channel blocker group (17.6 vs. 12.4% for thiazides and 15.5 vs. 19.6% for beta-blockers, in the ACE inhibitor vs. calcium-channel blocker groups). The incidence rate of new-onset AF was significantly lower in the ACE inhibitor treated group compared with the calcium-channel blocker treated group (HR, 0.85; 95% CI, 0.74–0.97). The average interval to the first onset of AF was 29.5 vs. 26.1 months (a difference of 3.4 months; 95% CI, 0.72–6.04) in the ACE inhibitor vs. calcium-channel blocker groups, respectively. Using the Kaplan–Meier method, event-free survival for AF was found to demonstrate a significant decrease in new-onset AF over the whole observation period (P = 0.0183). The potential benefit of ACE inhibition over calcium-channel blockade in patients with hypertension was also assessed by analysing the rate of AF-related hospitalization. During the entire study follow-up period, the incidence rate of AF-related hospitalization was 8.5 vs. 11.9 per 1000 patient-years for ACE inhibitors vs. calcium-channel blockers, respectively, with an incidence ratio for patients treated with an ACE inhibitor of 0.74 (95% CI, 0.62–0.89). Further analysis demonstrated that there was an incremental benefit of ACE inhibition over calcium-channel blockade in patients with a prior history of AF compared with patients without a previous episode of AF. Indeed, at the end of the entire follow-up period, the incidence ratio for patients with a prior history of AF who were treated with an ACE inhibitor was 0.55 (95% CI, 0.38–0.78), whereas in patients without a prior history of AF, the ratio was 0.82 (95% CI, 0.67–1.01). ACE inhibition was thus associated with a reduced incidence of AF and related hospitalization in hypertensive patients in a managed/usual care setting.

Perindopril and the second Canadian Trial on Atrial Fibrillation (CTAF-2)
Our cohort study of almost 11 000 patients with hypertension, as described above, demonstrated that ACE inhibition was associated with a reduced incidence of AF in a usual care setting.19 The bulk of the evidence to date suggests that blockade of RAS may be a novel target to prevent recurrence of AF in patients with hypertension. However, this has not been tested in an adequately powered prospective trial. The ongoing second Canadian Trial on Atrial Fibrillation (CTAF-2) is therefore testing the hypothesis that perindopril, a long-acting ACE inhibitor with a high affinity for tissue ACE and demonstrated anti-hypertensive efficacy, will be effective in preventing recurrences of AF in patients with hypertension. The primary objective of CTAF-2 is to evaluate the effect of perindopril 8 mg daily on the recurrence of AF in patients with systemic hypertension.

CTAF-2 is a prospective, multicentred, parallel-arm, placebo-controlled, double-blind study. A total of 320 participants are being recruited at ~30 sites in Canada. The main inclusion criteria are the presence of symptomatic paroxysmal or persistent (with an indication for cardioversion) AF of at least 10 min duration, with at least one episode with electrocardiographic documentation during the last 6 months, as well as a diagnosis of systemic hypertension. Patients are excluded if there is evidence of left ventricular systolic dysfunction with an ejection fraction of ≤45%, a myocardial infarction within the month prior to the selection visit, cardiac or thoracic surgery within the past 3 months or likely to be performed during the trial, AF secondary to an acute reversible condition (postoperative AF, hyperthyroidism), requirement of class I or class III anti-arrhythmic drug therapy, any medical condition requiring ACE inhibitor or angiotensin-receptor blocker therapy, renal insufficiency with serum creatinine of ≥180 µmol/L, known bilateral renal artery stenosis, serum potassium of ≥5.0 mmol/L, use of an ACE inhibitor or angiotensin-receptor blocker in the 3 months before the inclusion visit, or severely uncontrolled hypertension with systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at the inclusion visit (Table 1).


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  		Table 1 Inclusion and exclusion criteria for the second Canadian Trial of Atrial Fibrillation (CTAF-2)

 
Eligible patients whose written informed consent has been obtained are randomized to one of two treatment groups for 2 weeks: perindopril 4 mg per day or matching placebo. After 2 weeks, patients are re-evaluated for blood pressure control and tolerability to the study medication. If patients develop non-tolerable adverse reactions to the study medication, it is stopped and patients are allowed to remain in the study for intention-to-treat analysis. Patients tolerating the study medication who are randomized to the perindopril group then receive perindopril 8 mg per day, and patients in the placebo group remain on placebo, until the end of study. The duration of the double-blind treatment in CTAF-2 is 7–13 months (Figure 1). Patients with symptomatic orthostatic hypotension and patients for whom the investigator judges that there is a risk to increase the dose to 8 mg per day, continue on 4 mg per day for the duration of the study. During the course of the study, if symptomatic hypotension develops, investigators are first asked to decrease the dose or to stop anti-hypertensive drugs other than the study medication.


Figure 1
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  		Figure 1 Study design for the second Canadian Trial of Atrial Fibrillation (CTAF-2).

 
During the first 30 days after randomization, cardioversion is carried out if necessary in all patients with persistent AF. At the end of 30 days after randomization (from day 31), patients are re-evaluated. Follow-up for the primary end point commences at this point. Recurrence of AF at any point during the first 30 days after randomization is not considered as achieving the primary end point. Any recurrence occurring on day 31 (day 1 of follow-up) or later is considered as reaching the primary end point. Patients in persistent AF at the end of 30 days after randomization are considered to have achieved the primary end point on day 1 of follow-up. Patients are re-evaluated after 3 and 6 months, and up to 12 months after the follow-up phase has started (i.e. day 31). All study patients are provided with trans-telephonic monitoring devices to transmit event data directly to the electrocardiography (ECG) core laboratory.

All patients in CTAF-2 are considered for anticoagulation according to recently published guidelines.20 Class I and class III anti-arrhythmic drugs and ablative therapies are strongly discouraged during the course of the study; however, drugs formulated to slow the ventricular response to AF can be used throughout the study (digoxin, beta-blockers other than sotalol, and calcium-channel blockers). In terms of the treatment of hypertension, ACE inhibitors (other than the study medication) and angiotensin-receptor blockers are strongly discouraged during the course of the study. Diuretics, beta-blockers, and calcium-channel blockers can be used as needed in both groups to treat hypertension. Pharmacological therapy is adjusted in order to achieve blood pressure control as specified by recent guidelines.21,22

The primary efficacy end point will be the time from day 31 after randomization to the first sustained recurrence of AF, defined as any electrocardiographically documented AF by 12-lead ECG, trans-telephonic ECG monitoring, or 24 h Holter monitoring. Secondary efficacy end points are the proportion of patients without AF throughout the 6-month follow-up, the number of documented relapses of AF, and health care resource utilization including hospitalization for AF and cardioversion. The primary analysis will be an unadjusted comparison of time to first relapse of AF. Event-rate curves will be estimated by the Kaplan–Meier method and the difference between treatment groups will be assessed using the log-rank test. All statistical analyses will be performed using the intention-to-treat principle.


   Conclusion
Top
 Abstract
 Hypertension and atrial...
 Angiotensin-converting enzyme...
 Conclusion
References
 
Angiotensin-converting enzyme inhibitors are extensively prescribed to lower blood pressure in hypertensive patients, to control neuro-hormonal activation and remodelling and to decrease mortality in patients with impaired left ventricular function and heart failure. Recent developments in our understanding of the pathophysiology of AF have led to the evaluation of ACE inhibition as an anti-arrhythmic strategy. Clinical results also suggest that ACE inhibitors reduce the recurrence of AF. The potential medical and socio-economic impact of these findings warrants a dedicated prospective randomized trial. The ongoing CTAF-2 is testing the hypothesis that the ACE inhibitor perindopril will be effective in preventing recurrences of AF in patients with hypertension. Because of the high prevalence of both hypertension and AF in our society, a pharmacological intervention that can normalize blood pressure and prevent AF is likely to have a significant impact on health care.

Conflict of interest: J.-C.T. has received honoraria from Servier.


   References
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 Abstract
 Hypertension and atrial...
 Angiotensin-converting enzyme...
 Conclusion
 References
 

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